The research team, led by senior author You Wu with co-first authors Yangxin Zhao, Fangzheng Cao, Houwen Zhang, and Yu Liang, took an unusually comprehensive approach. Rather than studying one tissue or one disease in isolation, they integrated single-cell RNA-sequencing data from both COPD lung tissue and atherosclerotic plaques, then layered on a genetic technique called cell-type-specific Mendelian randomization. This combination allowed them to move beyond correlation and ask whether the immune programs shared by the two diseases are actually causal drivers of disease risk, using human genetic variation as a natural experiment.

Single-cell RNA sequencing allows researchers to measure gene activity in thousands of individual cells at once, revealing the cellular cast of a tissue rather than a blended average. When the team applied this lens to COPD lung samples, they found the expected mosaic of epithelial, endothelial, and stromal cells, but the most striking feature was the remodeling of the myeloid compartment, the branch of the immune system that includes macrophages and monocytes. Marker-gene analysis confirmed distinct transcriptional programs in these populations, and composition analysis showed that the balance of myeloid cells was substantially shifted in diseased lungs compared with healthy tissue.

Even more revealing was the cell-to-cell communication analysis. By mapping ligand-receptor interactions between cell populations, the researchers could reconstruct the signaling network of the COPD lung. Macrophages emerged as dominant hubs, ranking at the top by both the number of interactions and the strength of the signals exchanged. In other words, the inflamed lung is not simply awash with generic inflammation; it is organized around macrophages and monocytes that coordinate the inflammatory conversation. This finding aligns with earlier single-cell work showing that immune and epithelial remodeling are central features of COPD pathology.

When the team turned to atherosclerotic plaques, they found a remarkably similar picture. The plaque microenvironment was immune-rich and dominated by myeloid cells, and communication networks again placed macrophages at the center of the signaling web, whether interactions were counted or weighted by strength. The parallel was striking: two organs, two diseases, and yet the same cellular architecture, with macrophage-centered inflammatory circuits at the core of both. This convergence suggested that the lung-artery connection might be written into the shared behavior of myeloid cells rather than being a byproduct of smoking or aging alone.

The next step was to find the molecular threads connecting these two networks. Comparing upregulated genes across matched immune cell populations in both diseases, the researchers identified a surprisingly short list of overlaps. In CD4-positive T cells, the shared genes included IFITM1, IGLC2, EIF1AY, NR4A1, and ZBTB16; in macrophages, HSPA1B and SIGLEC12; in monocytes, OLR1, PER1, and CH25H; and in natural killer cells, IFITM1, FKBP5, and HSPA1B. The restricted overlap is itself informative: although the two diseases share a similar immune framework, local tissue environments impose substantial transcriptional divergence. The genes that do persist across both settings, however, may represent conserved nodes of pulmonary and vascular inflammation.

To test whether these shared genes matter causally, the team turned to Mendelian randomization, a method that uses naturally occurring genetic variants as proxies to ask whether higher expression of a gene influences disease risk. They drew expression quantitative trait loci from the oneK1K resource, a large single-cell eQTL dataset of circulating immune cells, and paired them with genome-wide association statistics for COPD and coronary atherosclerosis from the FinnGen biobank. Because macrophage-specific eQTLs were unavailable, circulating monocyte subsets served as genetically accessible proxies for macrophage-related programs, a reasonable substitution given that monocytes recruited to inflamed tissues differentiate into macrophage-like cells.

The results were strikingly patterned. HSPA1B, which encodes a stress-inducible member of the HSP70 family of molecular chaperones, emerged as the only gene with robust associations across both diseases. Genetically predicted HSPA1B expression in classical monocytes, the CD14-dominant cells that flood sites of sustained inflammation, was positively associated with risk of both COPD and coronary atherosclerosis, with odds ratios of 1.119 and 1.154 respectively and extraordinarily narrow confidence intervals. Yet in non-classical monocytes, the CD16-dominant cells that patrol the endothelium and support vascular homeostasis, the association flipped: higher HSPA1B expression was linked to lower risk of both diseases. In NK cells, HSPA1B expression was positively associated with COPD risk. Sensitivity analyses using the MR-Egger intercept test found no marked directional pleiotropy, strengthening confidence in the signal.

This cell-state-dependent pattern may be the study’s most important insight. HSPA1B is a chaperone involved in proteostasis and cellular stress adaptation, and HSP70 pathways have long been implicated in inflammatory regulation. The new data suggest its role is not uniform across the myeloid compartment. In classical monocytes, which fuel cytokine production and generate inflammatory macrophages in both lung and plaque, higher HSPA1B may reflect or reinforce persistence within a pro-inflammatory environment. In non-classical monocytes, which perform endothelial surveillance and resolution-related functions, the same gene may instead participate in a homeostatic stress-response program. The same molecule, in other words, appears to mean different things depending on which myeloid state expresses it, a nuance that bulk-tissue studies would have completely missed.

The authors are careful to note the limitations of a computational and genetic study. The single-cell data came from distinct tissue environments, the genetic validation relied on circulating rather than lesion-resident cells, and residual linkage disequilibrium confounding at the HSPA1B locus cannot be excluded without formal colocalization analysis. Mechanistic experiments will be needed to show how HSPA1B actually regulates myeloid and NK-cell function. Even so, the study delivers a compelling model: COPD and coronary atherosclerosis are bound together by a shared macrophage- and monocyte-centered immune architecture, and HSPA1B stands out as a cell-type-specific signal at the intersection of pulmonary and vascular inflammation. If future work confirms the mechanism, targeting stress-response programs in specific myeloid states could one day treat both diseases at once.

Subject of Research: Cell-type-specific genetic and single-cell analysis of shared immune mechanisms linking COPD and atherosclerosis

Article Title: Cell‐Type‐Specific HSPA1B Expression Links COPD and Atherosclerosis

Article References: Zhao, Y., Cao, F., Zhang, H., Liang, Y., & Wu, Y. (2026). Cell‐Type‐Specific HSPA1B Expression Links COPD and Atherosclerosis. Immunity, Inflammation and Disease, 14(9), Article e70530. https://doi.org/10.1002/iid3.70530

Image Credits: AI Generated

DOI: 10.1002/iid3.70530

Keywords: COPD, atherosclerosis, HSPA1B, macrophages, monocytes, Mendelian randomization, single-cell RNA sequencing, HSP70, inflammation, NK cells, myeloid cells, comorbidity